On the basis of rationale and recent findings in our Laboratory, we plan to synthesize C-nucleoside derivatives in Figure 1 to study their biophysical and biochemical nature for eventual applications of cancer- related chemotherapy. a) 5'-Hyrogenphosphonate and 5'-methylphosphonate derivatives of 5- (beta-D-ribofuranosyl)-nicotinamide, 6-(beta-D- ribofuranosyl)picolinamide, 4-(beta-D-ribofuranosyl)-isonicotinamide and 2-(beta-D-ribofuranosyl)isonicotinamide. (Class 1). These analogues will be studied for their anticancer activity in vitro and in vivo, in relation to their capacity to inhibit dehydrogenases, especially for the cancer related enzyme, IMP-dehydrogenase. b) NAD analogues in which the nicotinamide riboside moiety is displaced by a ribosylpyridine, and/or the pyrophosphate fragment is displaced by methylene bis(phosphonate). (Class 2). These analogues will be studied for their and their inhibitory activity against dehydrogenases (especially cancer related IMP-dehydrogenase), NAD-hydrolases and poly(ADP-ribose) polymerase. c) Homo-oligomers of 2'-deoxy-pseudo-isocytidine (c-CdR), 2'-deoxy-9- deazaadenosine (c-AdR), 2'-deoxy-9-deazaguanosine (c-GdR) and 2'-deoxy- 9-deazainosine (c-IdR). They are analogues of oligo-dT, -dC, -dA and - dG respectively (Class 3). These synthetic homo-oligomers of C- nucleosides will be studied as to whether they form a double helix with complementary homo-oligomers of C-nucleotides against nucleases will be studied. The physical and biochemical properties of the double helix will also be studied. d) Several hetero-oligomers containing a limited amount of C-nucleotides (Class 4). These synthetic oligomers will be studied if they form double helix with complementary oligomers of natural nucleotides. [e.g., TT...T-cT-TT...T with oligo-A]. The stability of these oligomers against nucleases will be studied. The physical and biochemical stabilities of the double helix will also be studied. e) Several 5'-di- and tri-phosphates of C-nucleosides to study for substrate specificity of various polymerizing enzymes (e.g., DNA- and RNA-polymerases, reverse transcriptases and polynucleotide phosphorylases). (Class 5) f) Large amounts of promising derivatives for further evaluation for eventual clinical application.